The corpus callosum (CC) can be absent or reduced in children with fetal alcohol syndrome (FAS) or alcohol related birth defect (ARBD). Histological studies have shown that the CC in the rat is also negatively affected by prenatal alcohol exposure that produces a wide range of blood alcohol concentrations (BACS) during the first, second, or first + second trimester equivalent. The abnormalities consist of temporally altered CC development, disorganization of laminar distribution of CC projection neurons (CCpn), misoriented CCpn, misshapen CCpn, and abnormal growth of apical and basilar dendrites of CCpn. Using the same histological techniques, a transgenic strain of mouse with total (-/-) deletion of the NMDA-R1 receptor has also been shown to have altered CC development which is opposite to that of rats with prenatal ethanol exposure. For NR1-/-, the alteration consists exclusively of accelerated CC development without the abnormal CCpn morphology or spatial disorganization. The goal of this project is to test the hypothesis that a significant in vivo mechanism in the negative effects of prenatal alcohol exposure on CC development is the action of ethanol on the NMDA-R1 receptor. This proposal will be used to obtain pilot data to support this hypothesis by giving prenatal alcohol exposure to pregnant NRl transgenic mice. Doses of alcohol that produce a High (>250 mg/dl) or Moderate (<200 mg/dl) BAC will be applied daily to NRl transgenic mice in a binge model during the first + second trimester equivalent. Controls will consist of NR1 transgenic mice that are ad-lib chow fed, or weight-matched pairfed mice that undergo the same handling and testing. A superficial morphological analysis of CC development will be carried out on offspring sacrificed at gestational day 15 and 17, and postnatal day 0 to tentatively pair the morphological phenotype with a presumed genotype. Following this initial analysis, tissue samples taken at the time of sacrifice will be analyzed by PCR amplification to determine the genotype of each pup. Only the NR1-/- and NR1+/+ offspring (the latter are controls) will undergo detailed histological analysis to evaluate the location, orientation, shape, and dendritic arbor of CCpn in all groups. There are three possible outcomes for the NR1-/- mice prenatally exposed to alcohol. 1) The CCpn will display the abnormalities typical of prenatal ethanol exposure, indicating that activation of the NMDA-R1 receptor is not a significant in vivo mechanism for prenatal ethanol neurotoxicity. 2) The CCpn will display the alteration typical of NR1-/-, indicating that activation of the NMDA-R1 receptor is a highly significant in vivo mechanism for prenatal ethanol neurotoxicity. 3) The CCpn will have intermediate effects in terms of temporal development, types of CCpn morphological abnormalities, or number of CCpn showing abnormalities. The results will be interpreted in comparison to existing data on the effects of ethanol on NMDA receptors in mature cells in vitro. The results of this proposal will serve as pilot data for a subsequent grant application to study possible mechanisms for neurotoxicity induced by fetal alcohol exposure, specifically the in vivo interaction of ethanol with receptors such as NMDA-R1 in terms of effects on CCpn and cortical cells at different stages of development.